Relapse remains problematic for alcoholics due, in part to the lack of effective pharmacotherapies. Identification of the precise molecular entities that contribute to relapse may facilitate rational drug design. Recent findings indicate a role of molecules that modulate signaling through G-proteins in relapse. This proposal focuses on the Activator of G-protein Signaling (AGS3). AGS3 expression increases during withdrawal from repeated cocaine administration. High AGS3 expression appears to induce neurochemistry resembling that found in addicted animals and AGS3 expression appears to increase the propensity to relapse to cocaine seeking behavior. AGS3 expression also increases in vitro after repeated ethanol exposure and in vivo after withdrawal from repeated ethanol administration. The role of AGS3 in alcoholism, however, remains to be elucidated. This proposal will determine the role of AGS3 and its signaling partner Gbetagamma in both the genetic and behavioral impact of repeated ethanol administration. Our objective is to determine if AGS3 contributes to relapse to ethanol seeking behavior. Our findings may aid pharmaceutical development for individuals suffering from alcoholism and alcohol abuse.